Recent findings suggest a novel positron emission tomography (PET) imaging approach determining epidermal growth factor receptor (EGFR) mutation status for improved lung cancer patient management

Recent findings suggest a novel positron emission tomography (PET) imaging approach determining epidermal growth factor receptor (EGFR) mutation status for improved lung cancer patient management. The findings are published in Science Translational Medicine.

The study was performed in the lab of Baozhong Shen, the TOF-PET/CT/MR Center of The Fourth Hospital of Harbin Medical University and the Molecular Imaging Research Center (MIRC) of Harbin Medical University.

The estimation of EGFR mutation status is essential for the identification of non-small cell lung carcinoma (NSCLC) patients who may benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs), and hence for improving therapeutic efficacy.

While several techniques are currently available to assess EGFR mutation status, these methods require tumor biopsies and can often fail or have poor reproducibility due to insufficient material for mutation analysis.

Additionally, intra- and inter-tumor heterogeneity over space and time makes it even more challenging to assess EGFR mutation status in real time. Plasma samples of patients with NSCLC is a less invasive method and has been used as surrogate tumor tissues for detecting genetic alterations.

However, many studies have found the inconsistency of EGFR mutation status in plasma DNA samples as compared to tumor tissue DNA samples. Plasma samples also cannot address the issue of expression heterogeneity (primary tumor vs. metastatic site(s)).

"How can we overcome the limitations of tumor tissue biopsy and plasma samples for detecting genetic alterations, and obtain comprehensive tumor EGFR profiling in real-time?" asked Dr. Baozhong Shen.

"Can this technique provide both EGFR mutation status information at the molecular level and precise anatomical information such as size, shape, NSCLC tumor location(s), and their relationship with adjacent structures?."

"Molecular imaging with PET shows the potential for non-invasively detecting cancer biomarkers in primary or metastatic tumors, and therefore for identifying patients who are likely to respond to specific treatments," Shen said.

"We wanted to develop a novel strategy with PET imaging for non-invasively determining EGFR mutation status in real-time, predict NSCLC patients who may benefit from EGFR-TKI therapy, and monitor EGFR-TKI treatment outcome."

The researchers designed and synthesized a novel small molecule PET tracer, 18F-MPG, with high specificity to activating EGFR mutant kinase. The preclinical studies showed that the newly developed 18F-MPG allows one to noninvasive and repeatedly detect activating EGFR mutational status in mouse models of NSCLC with high sensitivity and specificity.

More importantly, the researchers then translated this strategy to NSCLC patients. The first-in-human PET/CT imaging of 75 patients with 18F-MPG was performed to show that this tracer can be used as a companion diagnostic to identify NSCLC patients with EGFR activating mutant tumors (primary tumor or metastatic) with 84.3% accuracy.

The strategy achieves: (i) differentiating of tumor EGFR-activating mutation status with non-invasive, whole-body PET imaging; (ii) prediction of EGFR-TKIs sensitivity/resistance and patient survival; and (iii) monitoring of the dynamic changes in EGFR mutation status during therapy and guidance of precise treatment.

"There currently are no methods to predict EGFR-TKI therapy response in patients and design effective EGFR-TKIs therapies when a genetic test is not feasible or ambiguous." Shen said.

"With 18F-MPG PET/CT imaging, we were able to quantitate EGFR-activating mutation status in NSCLC patients (primary tumor or metastatic) and directly determine/visualize the location(s) and morphology of the NSCLCs."